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ASARM peptides: PHEX-dependent and -independent regulation of serum phosphate.
Am J Physiol Renal Physiol. 2011 Mar; 300(3):F783-91.AJ

Abstract

Increased acidic serine aspartate-rich MEPE-associated motif (ASARM) peptides cause mineralization defects in X-linked hypophosphatemic rickets mice (HYP) and "directly" inhibit renal phosphate uptake in vitro. However, ASARM peptides also bind to phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) and are a physiological substrate for this bone-expressed, phosphate-regulating enzyme. We therefore tested the hypothesis that circulating ASARM peptides also "indirectly" contribute to a bone-renal PHEX-dependent hypophosphatemia in normal mice. Male mice (n = 5; 12 wk) were fed for 8 wk with a normal phosphorus and vitamin D(3) diet (1% P(i) diet) or a reduced phosphorus and vitamin D(3) diet (0.1% P(i) diet). For the final 4 wk, transplantation of mini-osmotic pumps supplied a continuous infusion of either ASARM peptide (5 mg·day(-1)·kg(-1)) or vehicle. HYP, autosomal recessive hypophosphatemic rickets (ARHR), and normal mice (no pumps or ASARM infusion; 0.4% P(i) diet) were used in a separate experiment designed to measure and compare circulating ASARM peptides in disease and health. ASARM treatment decreased serum phosphate concentration and renal phosphate cotransporter (NPT2A) mRNA with the 1% P(i) diet. This was accompanied by a twofold increase in serum ASARM and 1,25-dihydroxy vitamin D(3) [1,25 (OH)(2)D(3)] levels without changes in parathyroid hormone. For both diets, ASARM-treated mice showed significant increases in serum fibroblast growth factor 23 (FGF23; +50%) and reduced serum osteocalcin (-30%) and osteopontin (-25%). Circulating ASARM peptides showed a significant inverse correlation with serum P(i) and a significant positive correlation with fractional excretion of phosphate. We conclude that constitutive overexpression of ASARM peptides plays a "component" PHEX-independent part in the HYP and ARHR hypophosphatemia. In contrast, with wild-type mice, ASARM peptides likely play a bone PHEX-dependent role in renal phosphate regulation and FGF23 expression. They may also coordinate FGF23 expression by competitively modulating PHEX/DMP1 interactions and thus bone-renal mineral regulation.

Authors+Show Affiliations

University of Tennessee Health Science Center, Memphis, Tennessee, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

21177780

Citation

David, Valentin, et al. "ASARM Peptides: PHEX-dependent and -independent Regulation of Serum Phosphate." American Journal of Physiology. Renal Physiology, vol. 300, no. 3, 2011, pp. F783-91.
David V, Martin A, Hedge AM, et al. ASARM peptides: PHEX-dependent and -independent regulation of serum phosphate. Am J Physiol Renal Physiol. 2011;300(3):F783-91.
David, V., Martin, A., Hedge, A. M., Drezner, M. K., & Rowe, P. S. (2011). ASARM peptides: PHEX-dependent and -independent regulation of serum phosphate. American Journal of Physiology. Renal Physiology, 300(3), F783-91. https://doi.org/10.1152/ajprenal.00304.2010
David V, et al. ASARM Peptides: PHEX-dependent and -independent Regulation of Serum Phosphate. Am J Physiol Renal Physiol. 2011;300(3):F783-91. PubMed PMID: 21177780.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - ASARM peptides: PHEX-dependent and -independent regulation of serum phosphate. AU - David,Valentin, AU - Martin,Aline, AU - Hedge,Anne-Marie, AU - Drezner,Marc K, AU - Rowe,Peter S N, Y1 - 2010/12/22/ PY - 2010/12/24/entrez PY - 2010/12/24/pubmed PY - 2011/4/22/medline SP - F783 EP - 91 JF - American journal of physiology. Renal physiology JO - Am. J. Physiol. Renal Physiol. VL - 300 IS - 3 N2 - Increased acidic serine aspartate-rich MEPE-associated motif (ASARM) peptides cause mineralization defects in X-linked hypophosphatemic rickets mice (HYP) and "directly" inhibit renal phosphate uptake in vitro. However, ASARM peptides also bind to phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) and are a physiological substrate for this bone-expressed, phosphate-regulating enzyme. We therefore tested the hypothesis that circulating ASARM peptides also "indirectly" contribute to a bone-renal PHEX-dependent hypophosphatemia in normal mice. Male mice (n = 5; 12 wk) were fed for 8 wk with a normal phosphorus and vitamin D(3) diet (1% P(i) diet) or a reduced phosphorus and vitamin D(3) diet (0.1% P(i) diet). For the final 4 wk, transplantation of mini-osmotic pumps supplied a continuous infusion of either ASARM peptide (5 mg·day(-1)·kg(-1)) or vehicle. HYP, autosomal recessive hypophosphatemic rickets (ARHR), and normal mice (no pumps or ASARM infusion; 0.4% P(i) diet) were used in a separate experiment designed to measure and compare circulating ASARM peptides in disease and health. ASARM treatment decreased serum phosphate concentration and renal phosphate cotransporter (NPT2A) mRNA with the 1% P(i) diet. This was accompanied by a twofold increase in serum ASARM and 1,25-dihydroxy vitamin D(3) [1,25 (OH)(2)D(3)] levels without changes in parathyroid hormone. For both diets, ASARM-treated mice showed significant increases in serum fibroblast growth factor 23 (FGF23; +50%) and reduced serum osteocalcin (-30%) and osteopontin (-25%). Circulating ASARM peptides showed a significant inverse correlation with serum P(i) and a significant positive correlation with fractional excretion of phosphate. We conclude that constitutive overexpression of ASARM peptides plays a "component" PHEX-independent part in the HYP and ARHR hypophosphatemia. In contrast, with wild-type mice, ASARM peptides likely play a bone PHEX-dependent role in renal phosphate regulation and FGF23 expression. They may also coordinate FGF23 expression by competitively modulating PHEX/DMP1 interactions and thus bone-renal mineral regulation. SN - 1522-1466 UR - https://www.unboundmedicine.com/medline/citation/21177780/ASARM_peptides:_PHEX_dependent_and__independent_regulation_of_serum_phosphate_ L2 - http://www.physiology.org/doi/full/10.1152/ajprenal.00304.2010?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -